This invention relates to miniaturized devices for the controlled exposure or release of molecules such as drugs and/or secondary devices such as sensors.
Microchip devices for chemical and drug delivery and for controlled exposure of reservoir contents have been described in detail in U.S. Pat. No. 5,797,898; U.S. Pat. No. 6,123,861; PCT WO 01/64344; and PCT WO 01/35928. One group of embodiments of these microchip devices provides active release or exposure of the contents of a reservoir in the substrate of the device. xe2x80x9cActivexe2x80x9d is used to refer to those embodiments in which release or exposure is initiated at a particular time by the application of a stimulus to the device or a portion of the device. Typically, the stimulus is applied to a reservoir cap covering the filled reservoirs. In one embodiment, thin reservoir caps consist of thin metal films. These films can be prepared from metals, such as gold, copper, silver and other metals, using microelectronic fabrication methods, such as evaporation and sputtering. To expose the contents of the reservoir to the environment outside of the reservoir, the barrier properties of the reservoir cap can be compromised by the electrochemical dissolution of the metal film. This dissolution typically is accomplished by maintaining the electrical potential of the metal electrode sufficiently anodic to oxidize the film, thereby forming soluble metal cations. In this embodiment, the stimulus applied to initiate active release or exposure is application of an electrical potential to the reservoir cap.
An important application for these active microchip devices is to serve as an implantable device for the delivery of drugs. Due to its small size, the microchip device may be implanted in the body in a variety of locations, including, but not limited to, under the skin and in the peritoneal cavity. The reservoir caps therefore will be directly exposed to one or more various bodily fluids in vivo, which can affect the electrochemical corrosion of the reservoir caps. In many complex fluids, such as biological fluids, the presence of electroactive molecules, such as some proteins, in the fluid may result in other reactions at or in close proximity to the electrode (i.e. the thin metal film). These reactions may reduce the rate of dissolution of the electrode. Because the electrochemical dissolution of the metal film should be rapid and of an extent sufficient to compromise the integrity of the reservoir cap, it would be advantageous to facilitate or enhance the corrosion of the metal electrode, particularly when the electrode is exposed to a biological fluid.
The use of a time varying potential has been used to facilitate electrochemical etching of materials. For example, U.S. Pat. No. 5,202,018 discloses the use of alternating anodic and cathodic potentials to etch semiconductors for the purpose of determining the composition and electrical properties as a function of depth. The alternating potential acts to produce a uniform etching of the material.
The electrochemical dissolution of metal films is a widely used industrial process used for the manufacture of items such as microelectronics packaging and connectors. For example, Frankenthal and Eaton, J. Electrochem. Soc., 123(5): 703-06 (1976) describes the use of a time-varying potential in the etching of platinum thin films used in the manufacture of microelectronic circuits. The etching was conducted in a solution of hydrochloric acid. The authors refer to U.S. Pat. No. 3,560,358 and No. 3,798,141 that involved the etching of noble metals using alternating current in solutions containing chloride and cyanide. In these manufacturing processes, the electrochemical dissolution of the metal is carried out in an electrolyte of known composition, and which is generally chosen to optimize one or more aspects of the etching process such as rate or surface finish.
Electrochemical methods can be used to prevent or remediate the fouling of metal surfaces. For example, U.S. Pat. No. 4,345,981 discloses the use of alternating potentials to reduce biofouling in conductive aqueous systems. The basis of this method is applying a potential suitably anodic to oxidize water at the electrode surface. The resultant generation of oxygen gas and hydrogen ions prevents fouling of the metal surface. In another example, U.S. Pat. No. 4,627,900 discloses the use of alternating potentials to remove nickel sulfide scale in reactors. The buildup of sulfide scale in vessels used to extract metals from mineral ores is remediated by applying a periodic potential to the reactor vessel to electrochemically convert the scale to soluble products.
Potential cycling has also been used as a means for preparing metal electrodes for analytical use. For example, Izumi, J. Electroanal. Chem., 301:151-60 (1991) discloses an electrochemical pretreatment to activate a gold electrode for electrochemical analysis. The pretreatment consists of cycling the electrode between xe2x88x920.04 and 1.41 volts versus a saturated calomel electrode (SCE) in a solution of hydrochloric acid. After this treatment, the potential required for the oxidation of ascorbic acid at the electrode was reduced and the current increased. This improvement in the properties of the electrode was attributed to a structural rearrangement of the gold surface.
None of these references are directed to facilitating electrode corrosion, particularly in a biocompatible or biological fluid, especially when in vivo.
It is therefore an object of the present invention to provide methods and devices for facilitating or enhancing the corrosion of a metal electrode in a biocompatible fluid, particularly for electrodes implanted in vivo.
It is a further object of the present invention to provide methods and devices for facilitating or enhancing the corrosion of thin metal film reservoir caps of active microchip devices.
It is another object of the present invention to enhance active release or exposure of reservoir contents from microchip devices, particularly microchip devices exposed to a complex, biocompatible fluid.
These and other objects, features, and advantages of the present invention will become apparent upon review of the following detailed description of the invention taken in conjunction with the drawings and the appended claims.
Methods and devices are provided for enhancing corrosion of a primary electrode in a biocompatible fluid. In a preferred embodiment, the method comprises (1) placing a metal electrode and a counter electrode in contact with an electroconductive biocompatible fluid to form an electrochemical cell; and (2) applying a time-varying potential, through the electrochemical cell, to the metal electrode, wherein the potential is characterized by a waveform having a maximum potential effectively anodic to meet or exceed the corrosion potential of the metal electrode, thereby corroding the metal electrode. The waveform also may preferably have a minimum potential effectively cathodic to be below the value where re-deposition of metal ions on the metal electrode can substantially occur. In this way, if a metal oxide is formed at the anodic potential, which passivates the surface and prevents further corrosion, then by making the potential cathodic, this oxide can be reduced and thus removed to expose the metal surface again.
The primary electrode also can be or comprise a polymer.
The electrode preferably comprises a reservoir cap of a microchip device for the release of molecules or exposure of device reservoir contents. Preferred reservoir contents include drugs, sensors, and combinations thereof.
The electrochemical cell can consist of two electrodes or can further comprise a reference electrode, which is placed in contact with the biocompatible fluid.
The biocompatible fluid can be a biological fluid, such as blood, plasma, extracellular matrix, lymph, interstitial fluid, serum, saliva, urine, semen, cerebrospinal fluid, and gastrointestinal fluids. The fluid can be in vivo or in vitro. Examples of other biocompatible fluids include saline solutions, buffer solutions, pharmaceutical carrier solutions, and fermentation broths.
The waveform can be, for example, a square wave, sine wave, sawtooth wave, triangle wave, and combinations thereof. The potential can be applied at essentially any frequency; however, a frequency between about 1 and 10 Hz is preferred.
In another embodiment, a microchip device is provided for the release or exposure of reservoir contents in any electroconductive fluid. The device includes (1) a substrate having reservoirs containing contents, wherein the reservoirs have reservoir caps which comprise a metal electrode; and (2) a means for applying a time-varying potential to the metal electrode in an amount effective to corrode the metal electrode when placed in an electroconductive fluid, wherein the means comprises a counter electrode. Preferably, the time varying potential is characterized by a waveform having a maximum potential effectively anodic to meet or exceed the corrosion potential of the metal electrode. In some embodiments, the waveform preferably has a minimum potential effectively cathodic to be below the value where re-deposition of metal ions on the metal electrode can substantially occur. The metal electrode preferably comprises gold, platinum, or silver, and preferably has a thickness between about 100 and 1000 nm.